The same clinical entities can be the cause of either primary or secondary amenorrhea, depending on the relationship between the onset of the particular disease or condition and the timing of pubertal development. Pregnancy should always be considered in the differential diagnosis of primary and secondary amenorrhea. Both hypothyroidism and hyperthyroidism may cause amenorrhea. Amenorrhea may be caused by disorders of hypothalamus, pituitary, ovaries, and outflow tract or by androgen excess. In general, disorders at the level of the hypothalamus or the pituitary gland present with low or normal levels of gonadotropins (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]) (hypogonadotropic hypogonadism), whereas high levels of gonadotropins suggest ovarian failure (hypergonadotropic hypogonadism).

Abnormalities at the level of the hypothalamus include hypothalamic suppression and deficiency in the pulsatile release of gonadotropin-releasing hormone. The most common diagnoses in this category are constitutional delay of puberty, stress, intense exercise, chronic or systemic illnesses (e.g., inflammatory bowel disease, cystic fibrosis, chronic renal failure), drug use (e.g., opiate, phenothiazine, marijuana), obesity, and eating disorders. Less common causes of hypothalamic amenorrhea include space-occupying lesions (e.g., craniopharyngioma, meningioma, glioma) and syndromes associated with hypothalamic dysfunction and pubertal delay such as
Kallmann syndrome (a familial disorder also associated with anosmia), Prader-Willi syndrome, and Laurence-Moon-Biedl syndrome.

Abnormalities at the level of the pituitary include idiopathic hypopituitarism, hyperprolactinemia, infiltrative processes, and infarction. Hyperprolactinemia may be caused by tumors, psychoactive drugs (e.g., haloperidol, phenothiazines, opiates, cocaine), breast stimulation, and renal failure. The most common pituitary tumor is the prolactin-secreting adenoma (prolactinoma). Prolactinomas classically present with galactorrhea, headache, and visual field loss. Although patients who have pituitary adenomas have elevated prolactin levels (usually greater than 100 ng/mL), galactorrhea is not a universal sign, and its absence does not preclude the presence of the tumor. Infiltrative processes may be caused by tuberculosis, sarcoidosis, histiocytosis, syphilis, or hemocromatosis. Infarction of the pituitary may be caused by postpartum hemorrhage (Sheehan syndrome), head trauma, or carotid artery aneurysm.

Abnormalities at the level of the ovaries can be divided into congenital and acquired causes. Among the congenital causes, Turner syndrome (45,XO), occurring in approximately 1 in 2,000 liveborn female infants, is the most common cause of ovarian failure. The classic features associated with this syndrome are short stature, webbed neck, widely spaced nipples, and cubitus valgus. Approximately one-half of patients with gonadal dysgenesis exhibit a mosaic karyotype (e.g., 45,XO/46,XX) or a structural abnormality of the X chromosome. Female adolescents with Turner mosaic or chromosomal incompetence may present with primary amenorrhea, secondary amenorrhea, or regular menstrual cycles. This spectrum is the result of varying amounts of functioning ovarian tissue. They may have none, some, or all of the stigmata of Turner syndrome, depending on what part of the X chromosome is affected. Other less common causes of congenital ovarian failure are pure gonadal dysgenesis, gonadotropin-resistant ovary syndrome, inborn deficiency of 17 alpha-hydroxylase, and galactosemia. Acquired causes of ovarian failure include premature ovarian failure (e.g., autoimmune oophoritis, radiation and/or chemotherapy), trauma, and other disorders (e.g., tuberculosis, sarcoidosis, gonoccocal salpingitis, mumps oophoritis).

Abnormalities at the level of the outflow tract include müllerian agenesis, androgen insensitivity, vaginal septum, imperforate hymen, spontaneous testicular regression, and specific gonadal enzyme deficiencies. Uterine synechiae should be considered in the postpartum or postabortal woman especially if she required vigorous curettage (Asherman syndrome). Other less common causes of uterine synechiae include complications from intrauterine device use and infections (e.g., pelvic inflammatory disease, tuberculosis, schistosomiasis). Müllerian agenesis or Mayer-Rokitansky-Küster-Hauser syndrome is the most common cause of primary amenorrhea resulting from genital tract anomaly. Accounting for as many as 15% of cases of primary amenorrhea, these patients are genetic and phenotypic females presenting with absence of a uterus and an incomplete vaginal pouch. The ovaries, breast, and pubic hair are normal.

The most common diagnosis of androgen excess is functional ovarian hyperandrogenism or polycystic ovary syndrome (PCOS). Associated physical findings such as acne, hirsutism, and obesity may be present, although they tend to be less prominent in adolescents than in adult women. Serum insulin levels may be elevated, and acanthosis nigricans, a cutaneous marker of hyperinsulinemia, may be present. Although polycystic ovaries are often found in adult patients, the appearance of normal ovaries on ultrasonography does not rule out this diagnosis, especially in younger women. Other less common causes of hyperandrogenism include late-onset 21-hydroxylase deficiency, sometimes referred to as nonclassic congenital adrenal hyperplasia, androgen-producing ovarian or adrenal tumors, ovarian stromal hypertrophy (hyperthecosis), and Cushing syndrome, as well as extrinsic sources of androgens, such as anabolic steroid use. Usually, in these cases, virilization is more severe than in PCOS and may include clitoromegaly and deepening of the voice. Box 91.1 summarizes the differential diagnosis of primary and secondary amenorrhea.

The patient’s history should cover general health including an overview of childhood growth and development, timing and progression of thelarche, adrenarche, menarche, and growth
velocity, signs and symptoms of chronic or systemic illnesses, eating habits including any change in weight, emotional stress including physical and sexual abuse, intensity and duration of exercise, sexual activity, hormonal contraceptive and barrier method use, and use of any other drugs or medications. In constitutional delay of puberty, a history in parents or older siblings of delayed menarche, height spurt, or sexual development often exists. Past medical history, including exposure to chemotherapy or pelvic or central nervous system radiation therapy, should be investigated. Review of systems can identify a history of vasomotor symptoms, hot flashes, rapid onset of virilizing symptoms, or thyroid dysfunction. Symptoms of significant headaches and visual disturbance may suggest intracranial tumor.